Synthesis Of A New PDE5Inhibitor-Avanafil

Male erectile dysfunction is a prevalent problem. There are many men sufferingfrom different extent of ED problems. PDE5is a member of PDE families，whichexists widly in corpus cavernosum smooth muscle. PDE5inhibitor is responsible forthe relaxation or contraction of corpus cavernosum smooth muscle through regulationcGMP and cAMP. Avanafil is a PDE5inhibitor, is used for the treatment of maleerectile dysfunction.The synthetic rout of avanafil was departed in6parts.(1) Using4-methyl-benzylamine as starting material，reacts with SO2Cl2thoughelectrophilic substitution reaction to get intermediate3-chloro-4-methyl-benzylamine.(2) Using s-methylisothiouronium sulfate and diethyl ethoxymethylenemalonateas starting materials to get ethyl4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate,and followed by chlorination to obtain ethyl4-chloro-2-(methylthio)Pyrimidine-5-car-boxylate.(3) Reduction of2-cyanopyrimidine to get2-aminomethylpyrimidine.(4) Reduction of L-proline to get L-prolinol.(5)4–chloro–2–(methylsulfanyl)pyrimidine–5–carboxylic acid ethyl ester, cond-ensed with3–chloro–4–methoxybenzylamine hydrochloride, followed by oxidation,substitution, hydrolysis of esters, condensation to obtain the target compoundavanafil.(6)4–chloro–2–(methylsulfanyl)pyrimidine–5–carboxylic acid ethyl ester, cond-ensed with3–chloro–4–methoxybenzylamine hydrochloride, followed by hydrolysisof esters, condensation, oxidation, substitution to obtain the target compound avanafil.On the basis of current documents and announcements，we have designed thesynthetic routs of avanafil，and though experiments we have already summarizedoptimal synthetic rout for intermediates and avanafil.